The seven-helix transmembrane G protein-coupled receptor (GPCR) family, encompassing more than 1,000 putative members, is crucially involved in cell-to-cell communication, in the response to environmental factors and hormones, and in the regulation of key cellular functions such as growth, differentiation and death. Due to such central roles, the malfunctioning of GPCRs (or of their signaling cascades) is associated to disease. A large majority of currently marketed drugs (including widely utilized anti-hypertensive, anti-thrombotic, anti-psychotic, anti-asthmatic and anti-ulcer drugs) indeed act through GPCRs.
Among all GPCRs, GPR17, is located at intermediate phylogenetic position between known purinergic P2Y and cysteinyl-leukotrienes (cysLTs) receptors (CysLTRs). Already characterized P2Y receptors and CysLTRs are activated, respectively, by extracellular nucleotides (Abbracchio et al., 2006) or cysLTs (Brink et al. 2003), two distinct families of inflammatory molecules acting as “danger signals” (Lecca et al., 2008), that sense damage in tissues and activate local reparative processes. These endogenous signaling molecules and their receptors mediate immune responses and ischemic/inflammatory conditions, including stroke and several currently incurable neurodegenerative diseases (Abbracchio et al., 2009). GPR17 signals through G(i) and inhibition of adenylyl cyclase and it has been previously shown that GPR17 responds to both uracil nucleotides and cysLTs (Ciana et al. 2006; Lecca et al., 2008; Pugliese et al. 2009). By employing a variety of in vivo rodent models of acute and chronic nervous system degenerative disorders, GPR17 has been validated as a novel target for the design of new drugs of potential use in human diseases characterized by neuronal and myelin dysfunction, including stroke, brain and spinal cord trauma and multiple sclerosis (Lecca et al. 2008; Ceruti et al. 2009; Chen et al. 2009). In a rat brain focal ischemia model, the selective in vivo knock down of GPR17 by anti-sense technology or P2Y/CysLTRs antagonists reduced progression of ischemic damage (WO2006/045476). Moreover, the involvement of GPR17 in the transition from oligodendrocyte precursors to mature oligodendrocytes expressing a myelinating phenotype has been demonstrated (Lecca et al., 2008; Chen et al. 2009; Fumagalli et al., 2011). These mature oligodendrocytes are able to repair a myelinic damage, by restoring the damaged myelinic envelope en-wrapping neuronal axons. All the published experimental data on GPR17 have been obtained using already available agonists and, in most cases, antagonists that have been purposely developed for other GPCRs.
Multiple Sclerosis (MS) is a chronic progressive disorder. It is an inflammatory disease in which the fatty myelin sheaths around the axons of the brain and spinal cord are damaged, leading to demyelination and scarring as well as a broad spectrum of signs and symptoms. MS is one of the central nervous system pathology with the largest diffusion. It affects about 1.3 million persons in the world, of which 400.000 in Europe. This incidence is worsened by the fact that MS affects still young peoples, who need chronic treatments, with a strong social and economical impact. The pharmacological treatments currently available are symptomatic and are not able to counteract MS progression. Immunomodulators are actually used and revealed a certain grade of effectiveness in acute treatments. However, they fail to solve the pathology. Moreover, all of the currently available therapeutics display significant side effects, both local and systemic.
Given the role played by GPR17 in the myelination process (Lecca et al. 2008, Chen et al. 2009; Fumagalli et al., 2011) and in the reduction of ischemic damage progression, there is the strong need to identify molecules capable to specifically bind said GPR17 receptor to be used as novel therapeutics in ischemia and MS or in any other condition characterized by demyelination. It is worth to note that for many of the conditions characterized by demyelination, such as schizophrenia, depression, Alzheimer's Disease, Parkinson's Disease, amyotrophic lateral sclerosis and Huntington's Disease, no curative therapy are currently available. Up to now, only non specific compounds have been tested on GPR17. In particular, CysLTRs antagonists have been used, selected from Montelukast, Pranlukast, Zafirlukast. These compounds are commercially available for asthma therapy. Alternatively, P2Y receptor antagonist have been used. Among these, Cangrelor and Ticagrelor. Ticagrelor has been approved by EMEA and FDA as a platelet aggregation inhibitor.
Rational drug development is a process to develop lead molecules, not by randomly screening thousands of molecules in the blind hope of finding one that shows the desired activity, but rather by deducing the active site of the target and devising a chemical that interacts with that site in the appropriate manner.
A crystallographic structure of GPR17 is not available so far. However, the crystallographic structures of the human CXC chemokine receptor type 4 (CXCR4) (Wu et al. 2010) is known and it is of particular interest for the purpose of the here claimed invention. In fact, the G protein-coupled chemokine receptor CXCR4 has been demonstrated to be phylogenetically and structurally very close to GPR17. CXCR4 crystallographic structure revealed a consistent homodimer with an interface including helices V and VI that may be involved in regulating signaling (Wu et al. 2010). The location and shape of the ligand-binding sites differ from other G protein-coupled receptors and are closer to the extracellular surface.
Here we describe families of compounds specifically able to interact with GPR17 receptor. Compounds and pharmaceutically acceptable salts thereof are useful in the treatment of pathological conditions such as stroke, heart disease, heart failure, high blood pressure, neurodegenerative diseases selected from, for example, Huntington's Disease, motor neuron diseases, leukodystrophies and MS.